Brugada syndrome masked by complete left bundle branch blockAbbas Hoteit MD, Marwan M. Refaat, MDDivision of Cardiology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, LebanonRunning Title: Brugada Syndrome masked by LBBBWords: 741 (excluding the title page and references)Keywords: Brugada syndrome, Left bundle branch block, Cardiovascular Diseases, Heart Diseases, Cardiac ArrhythmiasFunding: NoneDisclosures: NoneCorresponding Author:Marwan M. Refaat, MD, FACC, FAHA, FHRS, FASE, FESC, FACP, FAAMAAssociate Professor of MedicineDirector, Cardiovascular Fellowship ProgramDepartment of Internal Medicine, Cardiovascular Medicine/Cardiac ElectrophysiologyDepartment of Biochemistry and Molecular GeneticsAmerican University of Beirut Faculty of Medicine and Medical CenterPO Box 11-0236, Riad El-Solh 1107 2020- Beirut, LebanonUS Address: 3 Dag Hammarskjold Plaza, 8th Floor, New York, NY 10017, USAOffice: +961-1-350000/+961-1-374374 Extension 5353 or Extension 5366 (Direct)Brugada syndrome is a genetic disorder that affects the electrical activity of the heart. It is characterized by ST-segment elevations in the right precordial leads and right bundle branch morphology on ECG.1 These ECG changes are present in the absence of other causes of ST elevation or right bundle branch block morphology such as structural heart disease, ischemia, pacing or electrolyte disturbances.2 Clinical presentation varies between patients; it can range from asymptomatic changes seen on ECG to syncope, ventricular arrhythmias, and sudden cardiac death. 3So far, three types of ECG repolarization patterns have been identified (type 1, type 2, and type 3).4 Type 1 pattern is diagnostic of Brugada syndrome whereas types 2 and 3 are considered suggestive.5 According to the 2016 consensus conference of J-wave syndromes, the diagnosis of Brugada syndrome can only be made by finding a type 1 repolarization pattern. A type 1 pattern can either be spontaneous or unmasked by fever or medications. If it has been unmasked by either, then further evidence of patient clinical history, family history, or genetic testing should be present to fulfill a score of 3.5 or higher according to the Shanghai Scoring System.6 7 The Shanghai Scoring System does not include imaging; hence, even if changes in the right ventricle are found on cardiac MRI, they play no role in the diagnosis. 7In patients presenting with a non-type 1 pattern, a sodium channel blocker challenge is frequently used to unmask the type 1 pattern. Unmasking this pattern allows for diagnosis of Brugada syndrome which has a big impact on prognosis and management options. In some patients, an initial flecainide challenge test may be negative due to the variable sensitivity of this test. Some studies have shown that repeating the test may increase sensitivity, but, with increased risk of adverse drug effects. Prasad et al. showed that in patients with high clinical suspicion, family history of sudden cardiac death could serve as an indicator to repeat the flecainide test.5 8 9Several possible risk factors, that might predispose individuals to have a more severe presentation, have been identified. These include male gender, history of syncope, spontaneous type 1 pattern, family history of Brugada syndrome, and loss-of-function mutations in the SCN5A gene (which codes the alpha subunit of the cardiac sodium channel).10 Patients with SCN5A mutations tend to have earlier onset of symptoms, more noticeable electrophysiological defects (such as sick sinus syndrome and AV blocks), and increased risk of major arrhythmic events especially in Asian and Caucasian populations.11 High-risk patients are susceptible to sudden cardiac death; therefore, risk stratification helps in patient selection for Implantable Cardioverter Defibrillator placement.12 13In their article, Eduardo et al. presented the case of a 48-year-old lady who was initially diagnosed with Brugada syndrome after having a type 1 pattern on ECG. During follow-up, the patient’s ECG changed and showed a complete left bundle branch block instead of the typical type 1 pattern. Molecular studies showed the novel SCN5A p.1449Y>H variant and subsequent functional analysis showed a nonfunctional mutated membrane channel. SCN5A mutation can cause Brugada syndrome and conduction system abnormality as described in this lady. This variant generated minimal sodium currents. Such major decrease in current magnitude is associated with high penetrance as seen in the cases in this study. Although, during close follow-up, these patients did not have severe symptoms.14 What is most significant is that the authors presented a patient with Brugada syndrome who subsequently developed findings of complete left bundle branch block on ECG, making the diagnosis challenging due to masking of the type 1 pattern. This opens further discussion about diagnosis of the syndrome and potential maneuvers or procedures that would help unmask type 1 pattern under heart block. Since diagnosis can only be made by witnessing this pattern, this presents us a possibility where a diagnosis would be missed in such patients. SCN5A is the most common gene associated with this syndrome, accounting for around 20%. However, patient presentation varies widely with different mutations affecting channel function differently. In this case, the p.1449Y>H variant showed high penetrance and channel dysfunction despite relatively non-severe symptoms in patients affected. However, further observation is warranted to assess progression of the disease and the incidence of major arrhythmogenic events with aging and subsequent fibrosis. Further research is required to investigate the role of genetic studies in risk stratification and projecting patient clinical course depending on the presence of specific gene mutations/variants.References:Refaat MM, Hotait M, Scheinman MM. Brugada Syndrome. Card Electrophysiol Clin Mar 2016; 8(1): 239-45.Refaat M, Mansour M, Singh JP, Ruskin JN, Heist EK. Electrocardiographic Characteristics in Right Ventricular Versus Biventricular Pacing in Patients With Paced Right Bundle Branch Block QRS Pattern. J Electrocardiol Mar-Apr 2011; 44 (2): 289-95.Tse G, Liu T, Li KH, et al. Electrophysiological mechanisms of Brugada syndrome: insights from pre-clinical and clinical studies. Front Physiol 2016; 7: 467.Wilde, A. a. M.; Antzelevitch, C.; Borggrefe, M.; Brugada, J.; Brugada, R.; Brugada, P.; Corrado, D.; Hauer, R. N. W.; Kass, R. S.; Nademanee, K.; Priori, S. G. (November 2002). ”Proposed diagnostic criteria for the Brugada syndrome”. European Heart Journal . 23  (21): 1648–1654.Prasad S, Namboodiri N, Thajudheen A, Singh G, Prabhu MA, Abhilash SP, Mohanan Nair KK, Rashid A, Ajit Kumar VK, Tharakan JA. Flecainide challenge test: Predictors of unmasking of type 1 Brugada ECG pattern among those with non-type 1 Brugada ECG pattern. Indian Pacing Electrophysiol J. 2016 Mar-Apr;16(2):53-58. doi: 10.1016/j.ipej.2016.06.001. Epub 2016 Jun 20. PMID: 27676161; PMCID: PMC5031807.Antzelevitch C, Yan GX, Ackerman MJ, et al. J-wave syndromes expert consensus conference report: emerging concepts and gaps in knowledge.Heart Rhythm 2016;13:e295-324.Vutthikraivit W, Rattanawong P, Putthapiban P, Sukhumthammarat W, Vathesatogkit P, Ngarmukos T, Thakkinstian A. Worldwide Prevalence of Brugada Syndrome: A Systematic Review and Meta-Analysis. Acta Cardiol Sin. 2018 May;34(3):267-277. doi: 10.6515/ACS.201805_34(3).20180302B. Erratum in: Acta Cardiol Sin. 2019 Mar;35(2):192. PMID: 29844648; PMCID: PMC5968343.Gasparini M, Priori SG, Mantica M, Napolitano C, Galimberti P, Ceriotti C, Simonini S. Flecainide test in Brugada syndrome: a reproducible but risky tool. Pacing Clin Electrophysiol. 2003 Jan;26(1P2):338-41. doi: 10.1046/j.1460-9592.2003.00045.x. PMID: 12687841.Dubner S, Azocar D, Gallino S, Cerantonio AR, Muryan S, Medrano J, Bruno C. Single oral flecainide dose to unmask type 1 Brugada syndrome electrocardiographic pattern. Ann Noninvasive Electrocardiol. 2013 May;18(3):256-61. doi: 10.1111/anec.12052. PMID: 23714084; PMCID: PMC6932426.Bayoumy A, Gong MQ, Christien Li KH, Wong SH, Wu WK, Li GP, Bazoukis G, Letsas KP, Wong WT, Xia YL, Liu T, Tse G; International Health Informatics Study (IHIS) Network. Spontaneous type 1 pattern, ventricular arrhythmias and sudden cardiac death in Brugada Syndrome: an updated systematic review and meta-analysis. J Geriatr Cardiol. 2017 Oct;14(10):639-643. doi: 10.11909/j.issn.1671-5411.2017.10.010. PMID: 29238365; PMCID: PMC5721199.Chen C, Tan Z, Zhu W, Fu L, Kong Q, Xiong Q, Yu J, Hong K. Brugada syndrome with SCN5A mutations exhibits more pronounced electrophysiological defects and more severe prognosis: A meta-analysis. Clin Genet. 2020 Jan;97(1):198-208. doi: 10.1111/cge.13552. Epub 2019 May 6. PMID: 30963536.Probst, V., Veltmann, C., Eckardt, L., Meregalli, P. G., Gaita, F., Tan, H. L., Wilde, A. A. (2010). Long‐term prognosis of patients diagnosed with Brugada syndrome: Results from the FINGER Brugada Syndrome Registry. Circulation , 121 (5), 635–643. https://doi.org/10.1161/circulationaha.109.887026.Rattanawong P, Chenbhanich J, Mekraksakit P, Vutthikraivit W, Chongsathidkiet P, Limpruttidham N, Prasitlumkum N, Chung EH. SCN5A mutation status increases the risk of major arrhythmic events in Asian populations with Brugada syndrome: systematic review and meta-analysis. Ann Noninvasive Electrocardiol. 2019 Jan;24(1):e12589. doi: 10.1111/anec.12589. Epub 2018 Aug 20. PMID: 30126015; PMCID: PMC6931443.

Electrogram-guided Endomyocardial Biopsy Yield in Patients with Suspected Cardiac SarcoidosisAbbas Hoteit MD, Marwan M. Refaat, MDDivision of Cardiology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, LebanonRunning Title: Electrogram-guided Biopsy in Cardiac SarcoidosisWords: 819 (excluding the title page and references)Keywords: Cardiac Sarcoidosis, Heart Diseases, Cardiovascular Diseases, Cardiac ArrhythmiasFunding: NoneDisclosures: NoneCorresponding Author:Marwan M. Refaat, MD, FACC, FAHA, FHRS, FASE, FESC, FACP, FAAMAAssociate Professor of MedicineDirector, Cardiovascular Fellowship ProgramDepartment of Internal Medicine, Cardiovascular Medicine/Cardiac ElectrophysiologyDepartment of Biochemistry and Molecular GeneticsAmerican University of Beirut Faculty of Medicine and Medical CenterPO Box 11-0236, Riad El-Solh 1107 2020- Beirut, LebanonUS Address: 3 Dag Hammarskjold Plaza, 8th Floor, New York, NY 10017, USAOffice: +961-1-350000/+961-1-374374 Extension 5353 or Extension 5366 (Direct)Sarcoidosis is a multisystem disease that is characterized by T-cell mediated formation of noncaseating granulomas in affected organs. The disease commonly might involve hilar lymphadenopathy, lungs, liver, spleen, heart, and other organs. The natural course and prognosis of the disease generally depends on the extent of the disease and the organs affected where spontaneous remission occurs in around two-thirds of patient.1 Involvement of the heart is recognized in around 30% of patients and is associated with poor prognosis.2 The presentation of patients with cardiac sarcoidosis varies significantly; it can range from mild to severe disease such as heart failure and fatal arrhythmias. Patients with cardiomyopathies might require implantable cardiac defibrillators or cardiac resynchronization therapy for sudden death prevention.3,4 Cardiac sarcoidosis can either present alongside extracardiac manifestations or isolated.5Diagnosis of cardiac sarcoidosis presents a particular challenge since there is no gold standard diagnostic tool and the presentation is variable.6 There are no disease-specific biomarkers that can reliably be used for diagnosis. Clinicians typically rely on current published guidelines for diagnostic criteria of cardiac sarcoidosis such as those of Heart Rhythm Society (HRS) and the Japanese Ministry of Health and Welfare (JMHW). The revised JMHW criteria provide a diagnosis either through histological evidence on biopsy or through the fulfillment of major and minor criteria that do not include cardiac PET whereas the HRS criteria provide either a definite pathway for diagnosis through histology or a clinical pathway for diagnosis of probable cardiac sarcoidosis that includes both cardiac PET and CMR as criteria.7,8 A definitive diagnosis of cardiac sarcoidosis can be obtained if endomyocardial biopsy can show noncaseating granulomas in the context of suspected cardiac sarcoidosis and other granulomatous diseases are excluded. However, endomyocardial biopsy has a low sensitivity of 20-30% since it is limited by several factors such as technique, sampling, patchy distribution of granulomas, location of lesions, and stage of the disease at the time of biopsy.5 Areas of inflammation and scarring typically show abnormal electrogram morphology, hence, it is thought that electrogram guidance may help in increasing the yield of endomyocardial biopsies. Electrogram guidance would potentially help avoiding normal myocardium during biopsy leading to increased yield and sensitivity.9In their study, Ezzedine et al. assessed the diagnostic yield of electrogram-guided endomyocardial biopsy and investigated association between positive endomyocardial biopsy and prognosis in patients with suspected cardiac sarcoidosis.10 This retrospective observational study included seventy-nine patients between 2011 and 2019 who had suspected cardiac sarcoidosis based on clinical presentation and findings on late gadolinium-enhancement cardiac magnetic resonance and/or cardiac positron emission tomography-computed tomography with N-13 NH3 perfusion imaging and F-18 fluorodeoxyglucose. Biopsy was done in patients suspicious of cardiac sarcoidosis in patients without extracardiac sarcoidosis or those with extracardiac disease but atypical/equivocal findings of cardiac sarcoidosis on imaging and meeting criteria in HRS guidelines as per the routine practice in Mayo Clinic. Mapping of the heart was performed prior to biopsy with partial guidance based on pre-procedural cardiac imaging. In patients with no identifiable abnormalities on electrogram, biopsies were taken from areas corresponding to those with abnormalities on pre-procedural imaging. Collected specimens were processed according to protocol and assessed by a blinded specialist. These specimens were considered positive if there was a combination of non-necrotizing granulomas, interstitial fibrosis, and scatted eosinophils. The study showed that electrogram-guided endomyocardial biopsy was associated with an adequate negative predictive value but low positive predictive value. A diagnosis of probable cardiac sarcoidosis can be made in patients with extracardiac manifestations according to established guidelines whereas in patients with suspected isolated cardiac sarcoidosis this is more difficult and as such biopsies play a more major role here. This study showed that, when guided by electrograms, endomyocardial biopsies had a higher diagnostic yield (41%) than that established in literature around 20-25%. Utilizing both abnormalities seen on both electrograms and on CMR or PET showed the highest diagnostic yield in endomyocardial biopsies. This acts as an important point of consideration for further research because accurate and timely diagnosis is paramount due to the diagnostics challenges and poor prognosis seen in cardiac sarcoidosis.10Previous evidence had shown that a positive endomyocardial biopsy for sarcoidosis was associated with poor prognosis.11However, LVAD and transplantation-free survival was found to be similar regardless of status of endomyocardial biopsy in this study.10 The authors explained that this could be explained by earlier detection of disease, differences in treatment, or more subtle detection of areas of involvement through electrograms. This study was well conducted but has been limited by its nature of being a retrospective observational study. Also, mapping was mostly limited to the right ventricle which may have underestimated the diagnostic yield of biopsies. This study represents the management done in a single tertiary care center which may not represent the same practice in other institutions with different facilities. Further multicenter and prospective studies are warranted to corroborate the data here and assess diagnostic and therapeutic modalities and long-term outcomes in patients.ReferencesStatement on sarcoidosis. Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999. Am J Respir Crit Care Med Aug 1999 ;160(2):736-55.Sekhri V, Sanal S, Delorenzo LJ, Aronow WS, Maguire GP. Cardiac sarcoidosis: a comprehensive review. Arch Med Sci Aug 2011; 7(4):546-54.AlJaroudi WA, Refaat MM, Habib RH, Al-Shaar L, Singh M, Gutmann R, Bloom HL, Dudley SC, Ellinor PT, Saba SF, Shalaby AA, Weiss R, McNamara DM, Halder I, London B; for the Genetic Risk Assessment of Defibrillator Events (GRADE) Investigators. Effect of Angiotensin Converting Enzyme Inhibitors and Receptor Blockers on Appropriate Implantable Cardiac Defibrillator Shock: Insights from the GRADE Multicenter Registry. Am J Cardiol Apr 2015; 115 (7): 115(7):924-31.Refaat M, Mansour M, Singh JP, Ruskin JN, Heist EK: Electrocardiographic Characteristics in Right Ventricular Versus Biventricular Pacing in Patients With Paced Right Bundle Branch Block QRS Pattern. J Electrocardiol Mar-Apr 2011; 44 (2): 289-95.Isobe M, Tezuka D. Isolated cardiac sarcoidosis: Clinical characteristics, diagnosis and treatment. Int J Cardiol Mar 2015; 182:132-40.Ahmed AI, Abebe AT, Han Y, Alnabelsi T, Agrawal T, Kassi M, Aljizeeri A, Taylor A, Tleyjeh IM, Al-Mallah MH. The prognostic role of cardiac positron emission tomography imaging in patients with sarcoidosis: A systematic review. J Nucl Cardiol Jul 2021; doi: 10.1007/s12350-021-02681-z. Online ahead of print.Sharma A, Okada DR, Yacoub H, Chrispin J, Bokhari S. Diagnosis of cardiac sarcoidosis: an era of paradigm shift. Ann Nucl Med Feb 2020;34(2):87-93.Ha FJ, Agarwal S, Tweed K, Palmer SC, Adams HS, Thillai M, Williams L. Imaging in Suspected Cardiac Sarcoidosis: A Diagnostic Challenge. Curr Cardiol Rev 2020;16(2):90-97.Liang JJ, Hebl VB, DeSimone CV, Madhavan M, Nanda S, Kapa S, Maleszewski JJ, Edwards WD, Reeder G, Cooper LT , Asirvatham SJ. Electrogram guidance: a method to increase the precision and diagnostic yield of endomyocardial biopsy for suspected cardiac sarcoidosis and myocarditis. JACC Heart Fail Oct 2014;2(5):466-73.Ezzedine FM, Kapa S, Rosenbaum A, Blauwet L, Deshmukh AJ, AbouEzzeddine OF, Maleszewski JJ, Asirvatham SJ, Bois JP, Schirger JA, Chareonthaitawee P, Siontis KC. Electrogram-guided Endomyocardial Biopsy Yield in Patients with Suspected Cardiac Sarcoidosis and Relation to Outcome. J Cardiovasc Electrophysiol Jul 2021; In Press.Ardehali H , Howard DL, Hariri A, Qasim A, Hare JM, Baughman KL, Kasper EK. A positive endomyocardial biopsy result for sarcoid is associated with poor prognosis in patients with initially unexplained cardiomyopathy. Am Heart J Sep 2005 ;150(3):459-63.